De novo protein synthesis is required for long-term memory consolidation. Dynamic regulation of protein synthesis occurs via a complex interplay of translation factors and modulators. Many components of the protein synthesis machinery have been targeted either pharmacologically or genetically to establish its requirement for memory. The combination of ligand/light-gating and genetic strategies, that is, chemogenetics and optogenetics, has begun to reveal the spatiotemporal resolution of protein synthesis in specific cell types during memory consolidation. This review summarizes current knowledge of the macroscopic and microscopic neural substrates for protein synthesis in memory consolidation. In addition, we highlight future directions for determining the localization and timing of de novo protein synthesis for memory consolidation with tools that permit unprecedented spatiotemporal precision.